Controlled release sterile injectable aripiprazole formulation and method

ABSTRACT

A controlled release sterile freeze-dried aripiprazole formulation is provided which is formed of aripiprazole of a desired mean particle size and a vehicle therefor, which upon constitution with water and intramuscular injection releases aripiprazole over a period of at least about one week and up to about eight weeks. A method for preparing the controlled release freeze-dried aripiprazole formulation, and a method for treating schizophrenia employing the above formulation are also provided.

This application claims a benefit of priority from U.S. ProvisionalApplication No. 60/513,618 the entire disclosure of which is hereinincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a controlled release sterilefreeze-dried aripiprazole formulation, an injectable formulation whichcontains the sterile freeze-dried aripiprazole and which releasesaripiprazole over at least a one week period, a method for preparing theabove formulation, and a method for treating schizophrenia and relateddisorders employing the above formulation.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,006,528 to Oshiro et al. discloses7-[(4-phenylpiperazino)-butoxy] carbostyrils, which includearipiprazole, as dopaminergic neurotransmitter antagonists.

Aripiprazole which has the structure

is an atypical antipsychotic agent useful in treating schizophrenia. Ithas poor aqueous solubility (<1 μg/mL at room temperature).

U.S. Pat. No. 6,267,989 to Liversidge, et al. discloses a method forpreventing crystal growth and particle aggregation in nanoparticulatecompositions wherein a nanoparticulate composition is reduced to anoptimal effective average particle size employing aqueous millingtechniques including ball milling.

U.S. Pat. No. 5,314,506 to Midler, et al. relates to a process for thedirect crystallization of a pharmaceutical having high surface areaparticles of high purity and stability wherein impinging jet streams areemployed to achieve high intensity micromixing of particles of thepharmaceutical followed by nucleation and direct production of smallcrystals.

A long-acting aripiprazole sterile injectionable formulation has meritas a drug dosage form in that it may increase the compliance of patientsand thereby lower the rate of relapse in the treatment of schizophrenia.Examples of known long acting drug products for the treatment ofschizophrenia include haloperidol decanoate and fluphenazine decanoateboth of which have an ester compound of low water solubility dissolvedin sesame oil. Microcapsules containing Risperidone (WO95/13814) andOlanzapine (WO99/12549) are also known.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a sterilefreeze-dried aripiprazole formulation which upon constitution with waterfor injection releases aripiprazole, in therapeutic amounts, over aperiod of at least about one week, and preferably over a period of two,three or four weeks and up to six weeks or more. The freeze-driedaripiprazole formulation of the invention includes:

(a) aripiprazole, and

(b) a vehicle for the aripiprazole,

which formulation upon constitution with water forms an injectablesuspension which, upon injection, preferably intramuscularly, releasestherapeutic amounts of aripiprazole over a period of at least one week,preferably two, three or four weeks, and up to six weeks or more.

The freeze-dried aripiprazole formulation of the invention willpreferably include:

(a) aripiprazole,

(b) one or more suspending agents,

(c) optionally one or more bulking agents,

(d) optionally one or more buffers, and

(e) optionally one or more pH adjusting agents.

A mean particle size of the freeze-dried aripiprazole formulation withinthe range from about 1 to about 30 microns is essential in formulatingan injectable which releases aripiprazole over a period of at leastabout one week and up to six weeks or more, for example up to 8 weeks.

It has been found that the smaller the mean particle size of thefreeze-dried aripiprazole, the shorter the period of extended release.Thus, in accordance with the present invention, when the mean particlesize is about 1 micron, the aripiprazole will be released over a periodof less than three weeks, preferably about two weeks. When the meanparticle size is more than about 1 micron, the aripiprazole will bereleased over a period of at least two weeks, preferably about three tofour weeks, and up to six weeks or more. Thus, in accordance with thepresent invention, the aripiprazole release duration can be modified bychanging the particle size of the aripiprazole in the freeze-driedformation.

The term “mean particle size” refers to volume mean diameter as measuredby laser-light scattering (LLS) methods. Particle size distribution ismeasured by LLS methods and mean particle size is calculated from theparticle size distribution.

In addition, in accordance with the present invention, a controlledrelease sterile injectable aripiprazole formulation in the form of asterile suspension, that is, the freeze-dried formulation of theinvention suspended in water for injection, is provided which, uponinjection, preferably intramuscularly, releases therapeutic amounts ofaripiprazole over a period of at least one week, which includes:

(a) aripiprazole,

(b) a vehicle therefor, and

(c) water for injection.

The controlled release sterile injectable formulation of the inventionin the form of a sterile suspension allows for high drug loadings perunit volume of the formulation and therefore permits delivery ofrelatively high doses of aripiprazole in a small injection volume(0.1-600 mg of drug per 1 mL of suspension).

Further, in accordance with the present invention, a method is providedfor preparing the sterile freeze-dried aripiprazole formulationdescribed above which includes the steps of:

(a) preparing sterile bulk aripiprazole, preferably having a desiredparticle size distribution and mean particle size within the range fromabout 5 to about 100 microns,

(b) preparing a sterile vehicle for the sterile bulk aripiprazole,

(c) combining the sterile bulk aripiprazole and the sterile vehicle toform a sterile primary suspension,

(d) reducing the mean particle size of aripiprazole in the sterileprimary suspension to within the range from about 1 to about 30 microns,to form a final sterile suspension, and

(e) freeze drying the final sterile suspension to form a sterilefreeze-dried suspension of the aripiprazole of desired polymorphic form(anhydrous, monohydrate, or a mixture of both).

In carrying out the above method, the reduction of the mean particlesize of the sterile primary suspension to the desired mean particle sizeis carried out employing an aseptic wet milling procedure, whichpreferably is aseptic wet ball milling. Aseptic wet milling is essentialin forming a homogeneous and sterile aripiprazole formulation of desiredmean particle size distribution.

In addition, in accordance with the present invention, a method forfreeze drying the final sterile suspension of aripiprazole is providedwhich produces a sterile freeze-dried aripiprazole of desiredpolymorphic form, that is anhydrous, monohydrate, or a mixture of both.

Still further in accordance with the present invention, a method isprovided for treating schizophrenia and related diseases which includesthe step of administering to a patient in need of treatment therapeuticamounts of the above described controlled release injectablearipiprazole formulation.

As an unexpected observation, it has been discovered that a suspensionof aripiprazole suspended in an aqueous solvent system will maintain asubstantially constant aripiprazole drug plasma concentration whenadministered by injection; preferably as an intra-muscular injection. Nolarge “burst phenomenon” is observed and it is considerably surprisingthat a constant aripiprazole drug plasma concentration can be maintainedfrom one (1) to more than eight (8) weeks employing the aripiprazolesuspension of the invention. The daily starting dose for an orallyadministered aripiprazole formulation is fifteen (15) milligrams. Inorder to administer a drug dose equivalent to one (1) to more than eight(8) weeks of the oral dosage quantity requires the administration of avery large amount of the drug as a single dose. The aqueous aripiprazoleinjectable formulation of the invention may be administered to deliver.large amounts of the drug without creating patient compliance problems.

The aripiprazole injectable formulation of the invention may includeanhydrous or monohydrate crystalline forms of aripiprazole or anadmixture containing both. If the monohydrate is used, the maintenanceof an extended drug plasma concentration is possible.

The aripiprazole injectable formulation of the invention can beadministered as an aqueous ready-to-use suspension; however, byfreeze-drying this suspension a more useful drug product can besupplied.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 is a graph depicting mean plasma concentrations versus timeprofiles of the Example 1 formulation of the invention in rats;

FIG. 2 is a graph depicting mean plasma concentrations versus timeprofiles of the Example 1 formulation of the invention in dogs; and

FIG. 3 is a graph depicting mean plasma concentrations vs. time profilesof the Example 1 formulation of the invention in humans.

DETAILED DESCRIPTION OF THE INVENTION

The controlled release sterile injectable aripiprazole formulation ofthe invention will include aripiprazole in an amount within the rangefrom about 1 to about 40%, preferably from about 5 to about 20%, andmore preferably from about 8 to about 15% by weight based on the weightof the sterile injectable formulation.

As indicated, desired mean particle size of the aripiprazole isessential in producing an injectable formulation having the desiredcontrolled release properties of the aripiprazole. Thus, to producedesired controlled release, the aripiprazole should have a mean particlesize within the range from about 1 to about 30 microns, preferably fromabout 1 to about 20 microns, and more preferably for about 1 to about 10to 15 microns.

Where the desired controlled release period is at least about two weeks,up to six weeks or more, preferably about three to about four weeks, thearipiprazole will have a mean particle size within the range from about1 to about 20, preferably from about 1 to about 10 microns, morepreferably from about 2 to about 4 microns, and most preferably about2.5 microns. The aripiprazole having a mean particle size of about 2.5microns will have a particle size distribution as follows:

Preferred More Preferred 95% < 20 microns 95% < 8 microns 90% < 15microns 90% < 6 microns 50% < 10 microns 75% < 3 microns 10% < 2microns   50% < 1.5 microns  10% < 0.5 microns

The aripiprazole formulation of the invention will preferably be formedof:

A. aripiprazole,

B. a vehicle therefor, which includes:

-   -   (a) one or more suspending agents,    -   (b) one or more bulking agents,    -   (c) one or more buffers, and    -   (d) optionally one or more pH adjusting agents.

The suspending agent will be present in an amount within the range fromabout 0.2 to about 10% by weight, preferably for about 0.5 to about 5%by weight based on the total weight of the sterile injectableformulation. Examples of suspending agents suitable for use include, butare not limited to, one, two or more of the following: sodiumcarboxymethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, hydroxypropylethyl cellulose, hydroxypropylmethyl cellulose,and polyvinylpyrrolidone, with sodium carboxymethyl cellulose andpolyvinylpyrrolidone being preferred. Other suspending agents suitablefor use in the vehicle for the aripiprazole include various polymers,low molecular weight oligomers, natural products, and surfactants,including nonionic and ionic surfactants, such as cetyl pyridiniumchloride, gelatin, casein, lecithin (phosphatides), dextran, glycerol,gum acacia, cholesterol, tragacanth, stearic acid, benzalkoniumchloride, calcium stearate, glycerol monostearate, cetostearyl alcohol,cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkylethers (e.g., macrogol ethers such as cetomacrogol 1000),polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fattyacid esters (e.g., the commercially available Tweens® such as e.g.,Tween 20® and Tween 80® (ICI Specialty Chemicals)); polyethylene glycols(e.g., Carbowaxs 3350® and 1450®, and Carbopol 9340 (Union Carbide)),dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, collodialsilicon dioxide, phosphates, sodium dodecylsulfate,carboxymethylcellulose ti calcium, hydroxypropyl celluloses (e.g., HPC,HPC-SL, and HPC-L), methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethyl-cellulose phthalate,noncrystalline cellulose, magnesium aluminum silicate, triethanolamine,polyvinyl alcohol (PVA), 4-(1,1,3,3-tetramethylbutyl)-phenol polymerwith ethylene oxide and formaldehyde (also known as tyloxapol,superione, and triton), poloxamers (e.g., Pluronics F68® and F108®,which are block copolymers of ethylene oxide and propylene oxide);poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, whichis a tetrafunctional block copolymer derived from sequential addition ofpropylene oxide and ethylene oxide to ethylenediamine (BASF WyandotteCorporation, Parsippany, N.J.)); a charged phospholipid such asdimyristoyl phophatidyl glycerol, dioctylsulfosuccinate (DOSS); Tetronic1508® (T-1508) (BASF Wyandotte Corporation), dialkylesters of sodiumsulfosuccinic acid (e.g., Aerosol OT®, which is a dioctyl ester ofsodium sulfosuccinic acid (American Cyanamid)); Duponol P®, which is asodium lauryl sulfate (DuPont); Tritons X-200®, which is an alkyl arylpolyether sulfonate (Rohm and Haas); Crodestas F-110®, which is amixture of sucrose stearate and sucrose distearate (Croda Inc.);p-isononylphenoxypoly-(glycidol), also known as Olin-10G® or Surfactant10-G® (Olin Chemicals, Stamford, Conn.); Crodestas SL-40® (Croda, Inc.);and SA9OHCO, which is C₁₈H₃₇CH₂(CON(CH₃))—CH₂(CHOH)₄(CH₂OH)₂ (EastmanKodak Co.); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside;n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecylβ-D-maltoside; heptanoyl-N-methylglucamide;n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexylβ-D-glucopyranoside; nonanoyl-N-methylglucamide; n-nonylβ-D-glucopyranoside; octanoyl-N-methylglucamide;n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; and thelike.

Most of these suspending agents are known pharmaceutical excipients andare described in detail in the Handbook of Pharmaceutical Excipients,published jointly by the American Pharmaceutical Association and ThePharmaceutical Society of Great Britain (The Pharmaceutical Society ofGreat Britain (The Pharmaceutical Press, 1986), specificallyincorporated by reference. The suspending agents are commerciallyavailable and/or can be prepared by techniques known in the art.

Carboxymethyl cellulose or the sodium salt thereof is particularlypreferred where the desired mean particle size is about 1 micron orabove.

The bulking agent (also referred to as a cryogenic/lyophilize protectingagent) will be present in an amount within the range from about 1 toabout 10% by weight, preferably from about 3 to about 8% by weight, morepreferably from about 4 to about 5% by weight based on the total weightof the sterile injectable formulation. Examples of bulking agentssuitable for use herein include, but are not limited to, one, two ormore of the following: mannitol, sucrose, maltose, xylitol, glucose,starches, sorbital, and the like, with mannitol being preferred forformulations where the mean particle size is about 1 micron or above. Ithas been found that xylitol and/or sorbitol enhances stability of thearipiprazole formulation by inhibiting crystal growth and agglomerationof drug particles so that desired particle size may be achieved andmaintained.

The buffer will be employed in an amount to adjust pH of an aqueoussuspension of the freeze-dried aripiprazole formulation to from about 6to about 8, preferably about 7. To achieve such pH, usually the buffer,depending on type, will be employed in an amount within the range fromabout 0.02 to about 2% by weight, preferably from about 0.03 to about 1%by weight, and more preferably about 0.1% by weight based on the totalweight of the sterile injectable formulation. Examples of bufferssuitable for use herein include, but are not limited to, one, two ormore of the following: sodium phosphate, potassium phosphate, or TRISbuffer, with sodium phosphate being preferred.

The freeze-dried formulation of the invention may optionally include apH adjusting agent which is employed in an amount to adjust pH of theaqueous suspension of the freeze-dried aripiprazole within the rangefrom about 6 to about 7.5, preferably about 7 and may be an acid or basedepending upon whether the pH of the aqueous suspension of thefreeze-dried aripiprazole needs to be raised or lowered to reach thedesired neutral pH of about 7. Thus, where the pH needs to be lowered,an acidic pH adjusting agent which as hydrochloric acid or acetic acid,preferably hydrochloric acid, may be employed. When the pH needs to beraised, a basic pH adjusting agent will be employed such as sodiumhydroxide, potassium hydroxide, calcium carbonate, magnesium oxide ormagnesium hydroxide, preferably sodium hydroxide.

The freeze-dried aripiprazole formulations may be constituted with anamount of water for injection to provide from about 10 to about 400 mgof aripiprazole delivered in a volume of 2.5 mL or less, preferably 2 mLfor a two to six week dosage.

In carrying out the method for preparing the freeze-dried aripiprazoleformulation of the invention, it is required that everything be sterileso that sterile aripiprazole and sterile vehicle are combinedaseptically to form a sterile suspension and that the sterile suspensionbe freeze-dried in a manner to form sterile freeze-dried powder or cake.Thus, an aseptic procedure is employed to produce sterile bulkaripiprazole of desired particle size distribution. The sterile bulkaripiprazole will have a mean particle size within the range from about5 to about 100 microns, preferably from about 10 to about 90 microns.

Preferably, an impinging jet crystallization method is employed toproduce sterile aripiprazole of desired small particle size and a narrowsize distribution, high surface area, high chemical purity, highstability due to improved crystal structure, while employing continuousprocessing.

The impinging jet crystallization utilizes two jet streams that strikeeach other head-on. One of the streams carries a solution rich in thearipiprazole and the other carries an anti-solvent, such as water. Thetwo streams strike each other which allows rapid homogeneous mixing andsupersaturation due to high turbulence and high intensity of micromixingupon impact. This immediate achievement of supersaturation initiatesrapid nucleation. In general, the average crystal size decreases withincreasing supersaturation and decreasing temperature of theanti-solvent. Therefore, in order to obtain the smallest particle size,it is advantageous to have the highest possible concentration of therich solution and the lowest temperature of the anti-solvent.

The vehicle for the sterile bulk aripiprazole including suspendingagent, bulking agent, buffer, optional pH adjusting agent and water isprepared and subjected to sterilization. Thereafter, the sterile bulkaripiprazole and sterile vehicle are aseptically combined to form asterile primary suspension and the particle size of the aripiprazole isreduced to a desired level. This is preferably carried out employing anaseptic wet milling procedure wherein sterile particles of aripiprazoledispersed in the sterile vehicle are subjected to grinding means in thepresence of grinding media to reduce the particle size of thearipiprazole to within the range of about 1 to about 10 microns,depending upon desired controlled release period.

The aseptic wet milling procedure is preferably wet ball milling. Whenthe desired mean particle size of the aripiprazole is above about 1micron, the primary suspension (combined aripiprazole-vehicle) is passedthrough a wet ball mill a single time (single pass) at from about 5 toabout 15 L/hr, preferably from about 8 to about 12 L/hr, and morepreferably about 10 L/hr, to reduce mean particle size of thearipiprazole to within the desired range, for example, from about 1 toabout 5 microns.

In addition to ball mills, such as Dyno mills, other low and high energymills may be employed such as a roller mill, and high energy mills maybe employed such as Netzsch mills, DC mills and Planetary mills.However, it is essential that the milling procedure and equipmentemployed be capable of producing sterile aripiprazole formulation ofdesired mean particle size.

Other techniques for particle size reduction which may be employedinclude aseptic controlled crystallization, high shear homogenization,high pressure homogenization and microfluidization to produce particleshaving a mean particle size ranging from about 1 to about 100 microns.

The resulting final suspension is aseptically filled into sterile vialsand aseptically loaded into a sterilized freeze drier. It is essentialthat a carefully designed freeze drying cycle be applied in order toform and/or maintain the desired crystalline form of the aripiprazole,which is known to exist in monohydrate form (Aripiprazole Hydrate A) aswell as in a number of anhydrous forms, namely Anhydride Crystals B,Anhydride Crystals C, Anhydride Crystals D, Anhydride Crystals E,Anhydride Crystals F, and Anhydride Crystals G, all of which may beemployed in the formulation of the invention.

The aripiprazole monohydrate (grains) or hydrate as referred to belowemployed in the present invention has the physicochemical propertiesgiven in (1)-(5) below. This aripiprazole hydrate is describedhereinafter as “Aripiprazole Hydrate A”.

(1) It has an endothermic curve characterized by the appearance of asmall peak at about 71° C. and a gradual endothermic peak around 60° C.to 120° C.

(2) It has an ¹H-NMR spectrum which has characteristic peaks at1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H),2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt,J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H),6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

(3) It has a powder x-ray diffraction spectrum which has characteristicpeaks at 2θ=12.6°, 15.4°, 17.3°, 18.0°, 18.6°, 22.5° and 24.8°.

(4) It has clear infrared absorption bands at 2951, 2822, 1692, 1577,1447, 1378, 1187, 963 and 784 cm⁻¹ on the IR (KBr) spectrum.

(5) It has a mean grain size of 50 μm or less.

Aripiprazole Hydrate A is manufactured by milling conventionalaripiprazole hydrate.

Conventional milling methods can be used to mill the aripiprazolehydrate. For example, the aripiprazole hydrate can be milled in amilling machine. A widely used milling machine can be used, such as anatomizer, pin mill, jet mill or ball mill. Of these, the atomizer ispreferred.

Regarding the specific milling conditions when using an atomizer, arotational speed of 5000-15000 rpm could be used for the main axis, forexample, with a feed rotation of 10-30 rpm and a screen hole size of 1-5mm.

The mean grain size of the Aripiprazole Hydrate A obtained by millingshould normally be 50 μm or less, preferably 30 μm or less. Mean grainsize can be ascertained by the grain size measurement method describedhereinafter.

Grain Size Measurement: 0.1 g of the grains to be measured weresuspended in a 20 ml n-hexane solution of 0.5 g soy lecithin, and grainsize was measured using a size distribution meter (Microtrack HRA,Microtrack Co.).

The aripiprazole anhydride crystals employed in the present inventionhave the physicochemical properties given in (6)-(10) below. Thesearipiprazole anhydride crystals are referred to hereinafter as“Aripiprazole Anhydride Crystals B”.

(6) They have an ¹H-NMR spectrum which is substantially the same as the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 4. Specifically, they havecharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H).

(7) They have a powder x-ray diffraction spectrum which is substantiallythe same as the powder x-ray diffraction spectrum shown in FIG. 5.Specifically, they have characteristic peaks at 2θ=11.0°, 16.6°, 19.3°,20.3° and 22.1°.

(8) They have clear infrared absorption bands at 2945, 2812, 1678, 1627,1448, 1377, 1173, 960 and 779 cm⁻¹ on the IR (KBr) spectrum.

(9) They exhibit an endothermic peak near about 141.5° C. inthermo-gravimetric/differential thermal analysis (heating rate 5°C./min).

(10) They exhibit an endothermic peak near about 140.7° C. indifferential scanning calorimetry (heating rate 5° C./min).

Aripiprazole Anhydride Crystals B employed in the present invention havelow hygroscopicity. For example, Aripiprazole Anhydride Crystals Bemployed in the present invention maintain a water content of 0.4% orless after 24 hours inside a dessicator set at a temperature of 60° C.and a humidity of 100%.

Well-known methods of measuring water content can be used as long asthey are methods commonly used for measuring the water content ofcrystals. For example, a method such as the Karl Fischer method can beused.

The Aripiprazole Anhydride Crystals B employed in the present inventionare prepared for example by heating the aforementioned AripiprazoleHydrate A at 90-125° C. The heating time is generally about 3-50 hours,depending on heating temperature. The heating time and heatingtemperature are inversely related, so that for example the heating timewill be longer the lower the heating temperature, and shorter the higherthe heating temperature. Specifically, if the heating temperature ofAripiprazole Hydrate A is 100° C., the heating time should normally be18 hours or more or preferably about 24 hours. If the heatingtemperature of Aripiprazole Hydrate A is 120° C., on the other hand, theheating time can be about 3 hours. The Aripiprazole Anhydride Crystals Bof the present invention can be prepared with certainty by heatingAripiprazole Hydrate A for about 18 hours at 100° C., and then heatingit for about 3 hours at 120° C.

Furthermore, the Aripiprazole Anhydride Crystals B employed in thepresent invention are prepared for example by heating conventionalaripiprazole anhydride crystals at 90-125° C. The heating time isgenerally about 3-50 hours, depending on heating temperature. Theheating time and heating temperature are inversely related, as describedabove. Specifically, if the heating temperature of the aripiprazoleanhydride crystals is 100° C., the heating time can be about 4 hours,and if the heating temperature is 120° C. the heating time can be about3 hours.

The aripiprazole anhydride crystals which are the raw material forpreparing the Aripiprazole Anhydride Crystals B employed in the presentinvention are prepared for example by Method a or b below.

Method A:

Aripiprazole Anhydride Crystals B are prepared by well-known methods, asby reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril with1-(2,3-dichlorophenyl) piperidine and recrystallizing the resulting rawaripiprazole crystals with ethanol as described in Example 1 of JapaneseUnexamined Patent Publication No. 191256/1990.

Method B:

Aripirazole Anhydride Crystals B are prepared by heating conventionalaripiprazole hydrate at a temperature of at least 60° C. and less than90° C. The heating time is generally about 1-30 hours, depending onheating temperature. The heating time and heating temperature areinversely related, as described above. Specifically, if the heatingtemperature of the aripiprazole hydrate is about 60° C., the heatingtime can be about 8 hours, while if the heating temperature is 80° C.,the heating time can be about 4 hours.

Method b is described in the Proceedings of the 4th Japanese-KoreanSymposium on Separation Technology (Oct. 6-8, 1996).

Furthermore, the Aripiprazole Anhydride Crystals B employed in thepresent invention are prepared for example by heating conventionalaripiprazole hydrate at 90-125° C. The heating time is generally about3-50 hours, depending on heating temperature. The heating time andheating temperature are inversely related. Specifically, if the heatingtemperature of the aripiprazole hydrate is 100° C., the heating time canbe about 24 hours, while if the heating temperature is 120° C., theheating time can be about 3 hours.

The aripiprazole hydrate which is the raw material for preparing theAripiprazole Anhydride Crystals B employed in the present invention isprepared for example by Method c below.

Method C:

Aripiprazole hydrate is obtained by dissolving the aripiprazoleanhydride crystals obtained by Method a above in a hydrous solvent, andheating and then cooling the resulting solution. Using this method,aripiprazole hydrate is precipitated as crystals in the hydrous solvent.

An organic solvent containing water is usually used as the hydroussolvent. The organic solvent should be one which is miscible with water,such as for example an alcohol such as methanol, ethanol, propanol orisopropanol, a ketone such as acetone, an ether such as tetrahydrofuran,dimethylformamide, or a mixture thereof, with ethanol being particularlydesirable. The amount of water in the hydrous solvent can be 10-25% byweight of the solvent, or preferably close to 20% by weight.

As mentioned above, the Aripiprazole Anhydride Crystals B employed inthe present invention are prepared by heating at 90-125° C. of theAripiprazole Hydrate A, conventional aripiprazole anhydride crystals orconventional aripiprazole hydrate, and the Aripiprazole Hydrate A,conventional aripiprazole anhydride crystals or conventionalaripiprazole hydrate may be used either individually or in combination.

The above crystal forms and other crystal forms of aripiprazole andmethods for making such crystal forms which may be employed hereininclude Hydrate A and Anhydride Crystals B as well as Anhydride CrystalsC, Anhydride Crystals D, Anhydride Crystals E, Anhydride Crystals F, andAnhydride Crystals G, as disclosed in PCT WO 03/26659, published Apr. 4,2003.

If the monohydrate form of the aripiprazole in the freeze-driedformulation is desired then the freeze drying cycle should includecooling of the formulation to about −40° C. at a suitable cooling rate.The primary drying should be performed at a temperature below around 0°C. and a suitable vacuum and duration.

If the anhydrous form of the aripiprazole in the freeze-driedformulation is desired then the freeze drying cycle should include threephases: freezing, primary drying, and secondary drying. The freezingphase should include cooling of the formulation to about −40° C. at asuitable cooling rate. The primary drying should be performed at atemperature below about 0° C. and a suitable vacuum and duration. Thesecondary drying should be performed at a temperature above about 0° C.and a suitable vacuum and duration.

The vials with the resulting freeze-dried aripiprazole suspension areaseptically stoppered under atmospheric pressure or partial vacuum andsealed.

Preferred injectable formulations in the form of aqueous suspensions areset out below:

Preferred Particle Size of about 1-10 Microns (Preferably about 2.5Microns)

Preferred Range % w/v Range % w/v (1) Sterile Aripiprazole - (meanparticle 1 to 40    8 to 15 size from about 1 to about 5 microns) (2)Suspending Agent (preferably 0.2 to 10    0.5 to 5carboxymethylcellulose Na salt) (3) Bulking Agent (preferably mannitol)1 to 10   4 to 5 (4) Buffer (preferably sodium 0.02 to 2    0.03 to 1phosphate) (adjust pH to about 6 to about 7.5) (5) pH Adjusting Agent(preferably As needed As needed sodium hydroxide) (adjust pH to about 6to about 7.5) (6) Water for injection As needed As needed

The aripiprazole will be present in the aqueous injectable formulationin an amount within the range from about 1 to about 40% (w/v),preferably from about 5 to about 20% (w/v), and more preferably fromabout 8 to about 15% (w/v), based on the total injectable formulation.

In preferred embodiments, the aripiprazole will be present in theaqueous injectable formulation to provide from about 50 to about 400mg/2 mL of formulation, preferably from about 100 to about 200 mg/mL offormulation.

Preferred individual dose injectable formulations in accordance with theinvention are as follows:

aripiprazole 100 mg 200 mg 400 mg carboxymethylcellulose 9 mg 9 mg 9 mgmannitol 45 mg 45 mg 45 mg Na phosphate 0.8 mg 0.8 mg 0.8 mg sodium qsto adjust qs to adjust qs to adjust hydroxide pH to 7 pH to 7 pH to 7water for qs to 1 mL qs to 1 mL qs to 1 mL injection

The aripiprazole formulations of the invention are used to treatschizophrenia and related disorders such as bipolar disorder anddementia in human patients. The preferred dosage employed for theinjectable formulations of the invention will be a single injection ormultiple injections containing from about 100 to about 400 mgaripiprazole/mL given one to two times monthly. The injectableformulation is preferably administered intramuscularly, althoughsubcutaneous injections are acceptable as well.

The following examples represent preferred embodiments of the invention.

EXAMPLES Example 1

An aripiprazole injectable (IM Depot) aqueous suspension (200 mgaripiprazole/2 mL, 200 mg/vial) was prepared as follows.

Aripiprazole Microsuspension Prepared by Media Milling

A microparticulate dispersion of aripiprazole was prepared using aDYNO®-MILL (Type KDL A, manufactured by Willy A. Bachoffen AGMaschinenfabrik, Basel, Switzerland).

The following ingredients were added to a 3 L glass jacketed vesselmaintained at 15° C. (±5° C.) to form a sterile primary suspension:

Aripiprazole 100 g Carboxymethylcellulose, Sodium Salt 7L2P 9.0 gMannitol 45 g Sodium Phosphate, Monobasic 0.8 g Sodium HydroxideSolution, 1N q.s. to adjust pH to 7.0 Water for Injection, USP q.s. to1040 g

The primary suspension was mixed at 500-1000 rpm for about 0.5 hour andthen at 300-500 rpm for an additional 1 hour under 20″Hg (±5″Hg) vacuum.

The media mill was prepared accordingly for the media milling process.The grinding container was partially filled with zirconium oxide beadsand the dispersion was passed through the mill operating at thefollowing conditions:

-   -   Grinding container: water jacketed 0.6 L stainless steel vessel    -   Coolant temperature: 15° C. (±5° C.)    -   Agitation speed: 2500 rpm    -   Grinding medium: 500 mL of very-high-density (VHD) zirconium        oxide beads    -   Suspension flow rate: 10 L/h    -   Milling time: 6 minutes

After a single pass milling, a sample of the processed suspension wasremoved and evaluated for particle size distribution using Horiba LA-910Laser Scattering Particle Size Distribution Analyzer. The particles weredetermined to have a mean particle size of 2.5 microns (μ) and thefollowing particle size distribution: 10%<0.4μ, 50%<1.6μ, 75%<3.3μ,90%<5.9μ, and 95%<7.6μ.

2.5 mL of the above suspension were aseptically filled into sterilizedvials which were then aseptically partially stoppered with sterilizedstoppers. The vials were aseptically transferred to a freeze dryer andlyophilized according to the following cycle:

(a) thermal treatment: freeze product at −40° C. over 0.1-1 h and keepat −40° C. for at least 3 h,

(b) cool the condenser to −50° C. or below,

(c) primary drying: lower chamber pressure to approximately 100 micronsHg and increase product temperature to −5° C. over approximately 2 h;continue primary drying at −5° C. and 100 microns Hg for at least 48 h,

(d) stopper the vials under atmospheric pressure or partial vacuum usingsterile nitrogen or air and remove from the freeze dryer,

(e) seal the vials with the appropriate seals and label.

Example 2

An aripiprazole injectable (IM Depot) aqueous suspension (200 mgaripiprazole/2 mL, 200 mg/vial) was prepared as follows.

Aripiprazole Microsuspension Prepared by Impinging Jet Crystallization

A microparticulate dispersion of aripiprazole was prepared usingimpinging jet crystallization.

The following procedure was employed to form a sterile bulkaripiprazole:

1. Suspend 100 g of aripiprazole in 2000 mL of 95% ethanol. Heat thesuspension to 80° C. until it becomes a clear solution.

2. Polish filter the aripiprazole solution into a holding vessel andmaintain at 80° C.

3. Polish filter 2000 mL water to another holding vessel and heat to 80°C.

4. Pump the aripiprazole solution through a 0.02 inch diameter nozzle at0.25 kg/min and impinge it with the 30° C. water pumped at 0.25 kg/minthrough a 0.02 inch diameter nozzle to form a crystal slurry which iscollected in an impingement vessel.

5. Agitate the newly formed crystal slurry in the impingement vesselwhile continuously transferring it to a receiver to maintain a constantvolume in the impingement vessel.

6. At the end of impingement, cool the slurry in the receiver to roomtemperature.

7. Filter the slurry.

8. Dry the wet cake at 35° C. under vacuum to yielding 100 g (96%recovery) of aripiprazole with reduced particle size (90%<100 μm).

The following ingredients were added to a 3 L glass jacketed vesselmaintained at 15° C. (±5° C.) to form a sterile primary suspension:

Aripiprazole (prepared by impinging jet 100 g crystallization):Carboxymethylcellulose, Sodium Salt 7L2P 9.0 g Mannitol 45 g SodiumPhosphate, Monobasic 0.8 g Sodium Hydroxide Solution, 1N q.s. to adjustpH to 7.0 Water, USP q.s. to 1040 g

The sterile suspension was mixed at 500-1000 rpm for about 0.5 hour andthen at 300-500 rpm for an additional 1 hour under 20″Hg (±5″Hg) vacuum.

The sterile suspension was found to contain particles having meanparticle size of 2.5 microns and the following particle sizedistribution:

10% < 0.4μ 50% < 1.6μ 75% < 3.3μ 90% < 5.9μ 95% < 7.5μ

2.5 mL of the above suspension were aseptically filled into sterilizedvials which were then aseptically partially stoppered with sterilizedstoppers. The vials were aseptically transferred to a freeze dryer andlyophilized according to the following cycle:

(a) thermal treatment: freeze product at −40° C. over 0.1-1 h and keepat −40° C. for at least 6 h,

(b) cool the condenser to −50° C. or below,

(c) primary drying: lower chamber pressure to approximately 100 micronsHg and increase product temperature to −5° C. over approximately 2 h;continue primary drying at −5° C. and 100 microns Hg for at least 48 h,

(d) stopper the vials under atmospheric pressure or partial vacuum usingsterile nitrogen or air and remove from the freeze dryer,

(e) seal the vials with the appropriate seals and label.

Example 3 (Animal PK Data) A. Single-Dose I.M. Depot Study in Rats

Aripiprazole I.M. depot formulation prepared in Example 1 was injectedinto the thigh muscle of fifteen rats (M-males, F-females) at doses of12.5, 25, and 50 mg/kg. Blood samples for the evaluation of systemicexposure after aripiprazole I.M. depot administration were collected ondays 1 (6 h postdose), 2, 4, 7, 10, 15, 22, 28, 36, and 43 and analyzedfor aripiprazole. FIG. 1 shows mean plasma concentrations vs. timeprofiles of aripiprazole in rats.

B. Single-Dose I.M. Depot Study in Dogs

The aripiprazole intramuscular (I.M). depot formulation prepared inExample 1 was injected into the thigh muscle of five dogs (M-males,F-females) at doses of 100, 200, and 400 mg. Blood samples for theevaluation of systemic exposure after aripiprazole I.M. depotadministration were collected on days 1 (10 and 30 minutes, and 1, 3,and 8 h postdose), 2, 4, 7, 10, 15, 22, 28, 36, and 42 and analyzed foraripiprazole. FIG. 2 shows mean plasma concentrations vs. time profilesof aripiprazole in dogs.

PK Profiles

Mean aripiprazole rats' serum concentration-time profiles are showngraphically in FIG. 1. Aripiprazole aqueous suspensions showed steadyserum concentration for at least 4 weeks in the rats' model.

Mean aripiprazole dogs' serum concentration-time profiles are showngraphically in FIG. 2.

Aripiprazole aqueous suspensions showed steady serum concentration for3-4 weeks in the dogs' model.

Example 4 (Human PK Data) Single-Dose I.M. Depot Study in Patients

Aripiprazole I.M. depot formulation prepared in Example 1 wasadministered intramuscularly to patients diagnosed with chronic, stableschizophrenia or schizoaffective disorder at. The study design includedadministration of a 5-mg dose of aripiprazole solution to all subjectsfollowed by a single dose of IM depot at 15, 50, and 100 mg per patient.Samples for PK analysis were collected until plasma concentrations ofaripiprazole were less than the lower limit of quantification (LLQ) for2 consecutive visits.

FIG. 3 shows mean plasma concentrations vs. time profiles ofaripiprazole in subjects 2 and 3 dosed with 15 mg of 1M Depot, andsubjects 4 and 5 who received 50 mg of IM Depot. In all casesaripiprazole plasma levels showed a fast onset of release and sustainedrelease for at least 30 days.

1.-31. (canceled)
 32. A controlled release sterile aripiprazoleinjectable formulation which upon injection releases aripiprazole over aperiod of at least one week, which comprises: (a) aripiprazole, (b) avehicle therefor, and (c) water for injection.
 33. The formulation asdefined in claim 32, wherein said vehicle comprises one or moresuspending agents.
 34. A controlled release aripiprazole injectableformulation which upon injection releases aripiprazole over a period ofat least one week, which comprises: (a) aripiprazole, and (b) a vehicletherefor, said vehicle comprising: (1) one or more suspending agents,(2) optionally one or more bulking agents, and (3) optionally one ormore buffering agents, and (c) water for injection.
 35. The formulationas defined in claim 34, further including a pH adjusting agent.
 36. Theformulation as defined in claim 34, in the form of a sterile suspension.37. The formulation as defined in claim 34, in the form of a sterilesuspension containing solids having a mean particle size within therange from about 1 to about 30 microns.
 38. The formulation as definedin claim 34, in the form of a sterile suspension containing solidshaving a mean particle size within the range from about 1 to about 20microns.
 39. The formulation as defined in claim 38, wherein the solidshave a mean particle size from about 1 to about 10 microns.
 40. Theformulation as defined in claim 34, designed to release aripiprazole ata controlled rate over a two week to four week period.
 41. Theformulation as defined in claim 34, in the form of a suspension where:(a) the aripiprazole is present in an amount within the range from about1 to about 40%, (b) the suspending agent is present in an amount withinthe range from 0.2 to about 10%, (c) the bulking agent is present in anamount within the range from about 2 to about 10%, (d) the buffer ispresent in an amount within the range from about 0.02 to about 2% toadjust the pH of the suspension within the range from about 6 to about7.5, all of the above % being % by weight/volume % based on the volumeof suspension.
 42. The formulation as defined in claim 34, wherein thesuspending agent is carboxymethylcellulose or its sodium-salt,hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropylethylcellulose, hydroxypropylmethyl cellulose, or polyvinylpyrrolidone, thebulking agent is mannitol, sucrose, maltose, lactose, xylitol orsorbitol, and the buffer is sodium phosphate, potassium phosphate orTRIS buffer.
 43. The formulation as defined in claim 34, which uponinjection releases aripiprazole over a two to four week periodcomprising: (a) aripiprazole, (b) carboxymethyl cellulose or its sodiumsalt, (c) mannitol, (d) sodium phosphate to adjust pH to about 7, (e)optionally sodium hydroxide to adjust pH to about 7, and (f) water forinjection.
 44. The formulation as defined in claim 42, comprisingaripiprazole 100 mg 200 mg 400 mg carboxymethylcellulose 9 mg 9 mg 9 mgmannitol 45 mg 45 mg 45 mg Na phosphate 0.8 mg 0.8 mg 0.8 mg sodium qsto adjust qs to adjust qs to adjust hydroxide pH to 7 pH to 7 pH to 7water for qs to 1 mL qs to 1 mL qs to 1 mL injection


45. The formulation as defined in claim 35, which permits delivery offrom about 0.1 to about 600 mg of aripiprazole per 1 mL of suspension.46. The formulation as defined in claim 32, wherein the aripiprazole isin anhydrous form or in the form of a monohydrate.
 47. The formulationas defined in claim 46, wherein the aripiprazole is in the form ofAripiprazole Anhydride Crystals B or Aripiprazole Hydrate A.
 48. Asterile freeze-dried controlled release aripiprazole formulation whichcomprises: (a) aripiprazole, and (b) a vehicle therefor, whichformulation upon constitution with water forms a sterile injectableformulation which upon injection releases aripiprazole over a period ofat least about two weeks.
 49. The freeze-dried formulation as defined inclaim 48, having a mean particle size within the range from about 1 toabout 10 microns which upon constitution with water for injectionreleases aripiprazole over a period of at least about three weeks. 50.The freeze-dried formulation as defined in claim 49, having a meanparticle size of about 2.5 microns.
 51. The freeze-dried formulation asdefined in claim 49, wherein said vehicle comprises: (a) one or moresuspending agents, (b) one or more bulking agents, and (c) one or morebuffering agents.
 52. The freeze-dried formulation as defined in claim51, further including a pH adjusting agent.
 53. The freeze-driedformulation as defined in claim 51, which upon constitution with waterand injection releases aripiprazole over at least about a three weekperiod, comprising: (a) aripiprazole, (b) carboxymethyl cellulose or itssodium salt, (c) mannitol, (d) sodium phosphate to adjust pH to about 7,and (e) optionally sodium hydroxide to adjust pH to about
 7. 54. Thefreeze-dried formulation as defined in claim 53, which uponreconstitution with water and injection releases aripiprazole over abouta four week period.
 55. The freeze-dried formulation as defined in claim54, wherein the aripiprazole is the form of anhydrous crystals or is inthe form of a monohydrate.
 56. A method for preparing the sterilefreeze-dried formulation as defined in claim 48, which comprises thesteps of: (a) preparing sterile bulk aripiprazole having a desiredparticle size distribution, (b) preparing a sterile vehicle for thesterile bulk aripiprazole, (c) combining said sterile aripiprazole andsaid sterile vehicle to form a sterile primary suspension which includesa sterile mixture of solids, (d) reducing the mean particle size of saidsterile mixture of solids in said sterile primary suspension to withinthe range from about 1 to about 10 microns to form a sterile finalsuspension, and (e) freeze drying said sterile final suspension to formthe freeze-dried formulation.
 57. The method as defined in claim 56,wherein the step of reducing the mean particle size of the sterilemixture of solids in said sterile primary suspension is carried outemploying wet milling.
 58. The method as defined in claim 57, whereinthe wet milling comprises wet ball milling.
 59. The method as defined inclaim 56, wherein said freeze drying step is carried out by cooling thesterile final suspension to about −40° and drying said cooled sterilefinal suspension at below about 0° C., to form freeze-dried aripiprazolein the form of its monohydrate.
 60. The method as defined in claim 56,where the freeze drying step of the sterile final suspension is carriedout in three phases: (1) a freezing phase which includes cooling of thesterile final suspension at about −40° C., (2) a primary drying phasewhich is performed at below about 0° C., and (3) a secondary dryingphase which is performed at above about 0° C., to form aripiprazole inanhydrous form.
 61. A method of treating schizophrenia, which comprisesadministering to a patient in need of treatment the formulation asdefined in claim
 34. 62. The method as defined in claim 61, wherein theformulation is administered intramuscularly or subcutaneously.